Developing an effective HIV vaccine presents extraordinary challenges given the diversity of the virus and the need for inducing both T and B cell responses that can provide broad coverage, have the right functional qualities and are long-lasting. During the past decade there has been substantial progress in developing various vaccine vectors and prime-boost combinations for inducing effective responses against HIV. However, it is critical to improve upon these promising vaccine strategies and to design novel approaches for enhancing vaccine-induced immunity. We have recently made the unexpected and surprising observation that rapamycin, a drug that targets mTOR (mammalian target of rapamycin) and is commonly used in transplant recipients as an imunosuppressive agent, can actually enhance not only the magnitude but also the functional qualities of vaccine-induced virus specific memory T cells. This adjuvant effect of rapamycin was seen in both mice and in non-human primates. We have also shown that rapamycin acts intrinsically in antigen specific T cells and identified mTOR as a major regulator of memory T cell differentiation. Thus, our working hypothesis is that targeting mTOR presents a novel strategy of modulating both the quantity and quality of vaccine-induceti memory Tcells. In addition to regulating memory T cell differentiation rapamycin can also decrease expression of CCR5, the HIV co-receptor, on activated CD4 T cells. Here we propose to modulate the mTOR pathway during vaccination to enhance generation of highly polyfunctional virus-specific CDS T cells and to induce virus-specific CD4 T cells that are CCR5' and are less susceptible to HIV/SIV infection. Taken together such a vaccination strategy may lead to enhanced control of HIV/SIV infection. To achieve our goal, we will investigate two important effects of rapamycin in rhesus macaques; 1) its safety and adjuvant effect in enhancing immunogenicity of AIDS vaccines and 2) its ability to enhance protection against a pathogenic SIV challenge. RELEVANCE